Sustained release formulations overcome the need for frequent administration of drug which enhance patient compliance and reduce drug toxicity. Since all drugs can not be absorbed throughout the gastrointestinal tract, they have to be targeted to the specific site where the absorption is more. Conventional enteric polymers suppress the release of drugs in stomach where the pH is acidic and release the drugs in near neutral or alkaline medium, prevalent in the intestinal region either immediately or in a sustained manner. The reverse enteric polymers can release the drug in stomach immediately and the release can not be sustained in view of the short residence of the dosage form in stomach. Gastroretentive drug delivery systems are needed for the delivery of drugs, which are better absorbed in the gastric region, have poor solubility in the intestinal region and/or are degraded by the enzymes present in intestine.
Gastroretentive dosage forms were developed by using various approaches in the past. One such approach was based on the mucoadhesive polymers. Ilium et el. disclosed in U.S. Pat. No. 6,207,197 B1 a bioadhesive formulation for the treatment of gastric ulcer caused by Helicobacter pylori. It comprised a drug core coated with rate controlling water insoluble polymer layer of ethylcellulose followed by bioadhesive outer layer of chitosan which was crosslinked with glutaraldehyde. The formulation was capable of adhering onto the gastric mucosa and releases the drug for an extended period of time within the stomach. Yeon et al. disclosed in WO2008/010690 A1 a bioadhesive composition which comprised multiple numbers of pellets coated with metformin hydrochloride followed by a bioadhesive polymer such as sodium alginate, sodium carboxymethyl cellulose, hydroxylpropylmethyl cellulose and chitosan. The pellets could be filled in the capsule or compressed into tablet along with the immediate release pellets which comprised glimepiride. WO2008/074108 A2 discloses a bioadhesive composition for the treatment of diabetes mellitus. It was prepared by wet granulating the mixture of metformin hydrochloride, bioadhesive polymer crosslinked polyacrylic acid and other ingredients and compressing the granules to form a tablet. The tablet was coated with a film forming hydrophilic polymer and glimepiride. The gelling behaviour of crosslinked polyacrylic acid led to adhesion of the dosage form to the gastric mucosa.
Mucoadhesive microspheres were developed by Liu et al. (Zhepeng Liu, Weiyue Lu, Lisheng Qian, Xuhui Zhang, Pengyun Zeng and Jun Pan, Journal of Controlled Release, 102, 135, 2005) for the treatment of gastric and duodenal ulcers associated with Helicobacter pylori. The microspheres were prepared by emulsification and evaporation method. Ethylcellulose was dissolved in acetone and the powder of crosslinked polyacrylic acid and the antibiotic amoxicillin were added and blended. The blend was dispersed in the light paraffin oil to form microspheres. Similar microspheres were prepared without using bioadhesive polymer as a control.
Cuña et al. developed mucoadhesive particles comprising complex of drug and anion exchange resin (M. Cuña, M. J. Alonsoa and D. Tones, European Journal of Pharmaceutics and Biopharmaceutics, 51, 199, 2001). The complex was prepared by dispersing the anion exchange resin particles in the aqueous medium containing amoxicillin. The complex formed was suspended in a dispersion of bioadhesive polymer, crosslinked polyacrylic acid and then emulsified in liquid paraffin. Gastric retention of the bioadhesive particles was evaluated in rats and the results showed that almost all the particles left the stomach within 2-3 hours. It was concluded that the mucoadhesive polymer could not enhance the gastric residence time.
Säkkinen et al. described a mucoadhesive gastro-retentive drug delivery system based on microcrystalline chitosan (Mia Säkkinen, Tiina Tuononen, Heidi Jürjenson, Peep Veski and Martti Marvol, European Journal of Pharmaceutical Sciences, 19, 345, 2003). In vivo study on human volunteers showed that the formulations did not adhere onto the gastric mucosa and they were passed onto the intestinal region. The result was further confirmed by gamma scintigraphy study (Mia Säkkinen, Janne Marvola, Hanna Kanerva, Kai Lindevall, Maija Lipponen, Tommi Kekki, Aapo Ahonen and Martti Marvola, European Journal of Pharmaceutics and Biopharmaceutics, 57, 133, 2004). Also the potential risk of oesophagus adhesion of chitosan particles was found by Säkkinen et al. (Mia Säkkinen, Janne Marvola, Hanna Kanerva, Kai Lindevall, Aapo Ahonen and Martti Marvola, European Journal of Pharmaceutics and Biopharmaceutics, 57, 145, 2004).
As described in the above disclosures the mucoadhesive gastroretentive delivery systems are not reliable as the adhesion to gastric mucosa is unpredictable. The adhesive property of polymers was affected due to their interaction with biological components present in the stomach. Also it was found that the adhesive strength was not adequate to withstand the mechanical action caused by the presence of food in the stomach.
Another approach to attain gastric retention was keeping the dosage form away from the pylorus valve. This was achieved by making the dosage form which can float on the gastric fluid. Such a floating dosage form was disclosed by Besse in US 200110046473 A1 which comprised a drug, a hydrophilic polymer like hydroxypropylmethyl cellulose and gas generating agent. The floating tablet was prepared by mixing the said components and other ingredients and then compressing into the tablet. Mahendra et al. disclosed in EP 1745775 A1 a floating dosage form which comprised a drug, a weak gelling polymer like sodium carboxymethyl cellulose, a strong gelling polymer like hydroxypropylmethyl cellulose, gas generating agent and other ingredients. Similarly, Chavanpatil et al. (Mahesh Chavanpatil, Paras Jain, Sachin Chaudhari, Rajesh Shear and Pradeep Vavia, International Journal of Pharmaceutics, 304, 178, 2005), Lohray et al. in US 2006/0013876 and Pascal et al in WO2006/063858 disclose floating dosage form variants with and without gas generating agents and low density buoyant particle composition respectively.
Atyabi et al. described floating microcapsules as a gastroretentive drug delivery system (F. Atyabi, H. L. Sharma, H. A. H. Mohammad and J. T. Fell, Journal of Controlled Release, 42, 105, 1996). The microcapsules were based on the ion exchange resin which comprised sodium bicarbonate and an anionic inorganic compound sodium pertechnetate as a model drug. The capsules were coated with Eudragit RS which helped to retain the generated gas within the microcapsules. The gastric retention of coated and uncoated microcapsules was compared and the results showed that the coated capsules could float on the gastric fluid for longer duration than uncoated microcapsules. However, the system is limited to only ionic drugs as they are capable forming ionic complex with oppositely charged resin beads.
The major draw back associated with floating dosage form is that they require fluid in the stomach. When the stomach gets emptied by gastric motility, there is no fluid in the stomach on which the dosage could float. Numerous dosage forms were developed which could be retained in the stomach even after gastric motility action. These dosage forms were designed in such way that their dimensions were larger than opened pylorus. Such dosage forms could be folded to small size and then filled into capsule for ease of administration. The expansion of dosage forms into large dimension occurred once they were placed in the gastric fluid as disclosed in U.S. Pat. Nos. 4,735,804, 5,002,772 and EP 1235557.
Although, numerous expandable dosage forms have been developed for gastroretentive drug delivery, their reliability and safety is still a matter of concern. For example premature expansion of delivery device before reaching the stomach may lead to oesophagal obstruction. Also the failure of the device to expand may result in emptying of the dosage form from the stomach. This may lead to obstruction and injuries in the intestinal tract. Another problem associated with these systems is storage in the folded form, as it reduces the resilience and limits rapid unfolding in the gastric fluid. The construction of these devices, is difficult and needs special equipments.
Gröning et al. (Rüdiger Gröning, Michael Berntgen, Manolis Georgarakis, European Journal of Pharmaceutics and Biopharmaceutics, 46, 285, 1998) described a magnetic depot tablet system for gastroretentive drug delivery. It comprised a circular magnet coated with three layers one over another comprising carnauba wax layer, an inner layer comprising the major portion of drug, hydroxypropylmethyl cellulose and magnesium stearate followed by an outer layer comprising minor portion of the drug, hydroxypropylmethyl cellulose, lactose and magnesium stearate. In-vivo study was conducted in human volunteers by administering them with the magnetic depot tablets.
The movement of tablets was controlled by an external magnet which was fixed on the subject body. The results showed that the dosage forms retained in the stomach for 12 hours and released the content. However, the practical utility of the system is limited, since the patient needs to carry an external magnet to manipulate the location of the magnetic depot tablet.
Chen et at (Jun Chen, William E. Blevins, Haesun Park, and Kinam Park, Journal of Controlled Release, 64, 39, 2000) described a superporous hydrogel composition for gastroretentive drug delivery. The delivery system was based on the copolymer of acrylamide and sulfopropyl acrylate crosslinked with methylenebisacrylamide. The hydrogel was prepared in the presence of gas generating agent and other ingredients with porous structure. The hydrogel swelled into large size within a shorter period of time. In-vivo studies were conducted in dogs and the results showed that the hydrogels were retained in the stomach upto 32 hours but fragmented in between 27 and 32 hours. However, the loading of the drug within the hydrogel system and its release behaviour was not reported.
Wong et al, disclosed in U.S. Pat. No. 6,548,083 B1 a gastroretentive drug delivery system which swelled to large size upon contacting with simulated gastric fluid. It was prepared by granulating the mixture of active agent, water soluble polymer, water insoluble polymer and other ingredients and then compressing into the caplet shaped tablet. The tablet also comprised at least one band of polyolefin material which was fitted onto the tablet in such way that it located at midpoint. Swelling of tablet would enhance the gastric retention. The use of polyolefin band restricts their utility as it may not be biocompatible. Shell disclosed in U.S. Pat. No. 5,582,837 a dosage form which comprised multiple pellets. The pellets were prepared by mixing the hydrophilic soluble polymer like hydroxypropyl cellulose, the drug and other ingredients and compressing into pellets. A combination of pellets dispersed within a tablet or filled in a capsule to form a dosage form. The pellets were in the size of 3-9 mm and they exited immediately once the dosage form was placed in the aqueous medium. The pellets swelled upto 2 times in 1-3 hours and swelled upto 5 times in about 5 hours. The swollen particles released the drug by diffusion over an extended period of time. It was claimed that the swelled particles could not pass through the pylorus so that it would be retained in the stomach.
The release of sparingly soluble drugs by diffusion is dependent on the amount of fluid present in the stomach. In this case the disclosed composition in U.S. Pat. No. 5,582,837 may not be effective as it released the drug by diffusion. An alternative composition as disclosed by Shell et al. in U.S. Pat. No. 5,972,389 comprised an erodible polymer like polyethylene oxide wherein the drug releases occurred by erosion of the polymer. The preferred shapes of the said dosage forms to obtain the gastric retention were described by Merner et al. in U.S. Pat. No. 6,488,962. The gastroretentive tablet comprising hydroxylpropylmethyl cellulose did not swell significantly in the gastric fluid as compared to tablet comprising polyethylene oxide. However, polyethylene oxide eroded faster and an initial burst release of the drug was observed from the tablet. The amount of polyethylene oxide needed to achieve the desired level of swelling of the tablet was high and it is not acceptable in view of the polymer toxicity. In the gastroretentive composition disclosed by Gusler et al in U.S. Pat. No. 6,723,340 B2 a portion of polyethylene oxide was replaced by hydroxypropylmethyl cellulose to overcome this problem.
The prior art review shows several approaches that have been tried to provide a gastroretentive dosage forms that achieve the objective of releasing drug within the stomach; the disadvantages of such delivery systems were varied such as lack of mucoadhesion, the need of fluid to remain floating and the risk of gastrointestinal tract obstruction. Swellable gastroretentive dosage forms comprising pH independent polymers like hydroxypropylmethyl cellulose and polyethylene oxide which, are associated with low swelling and initial burst release of the drug respectively. It is also essential that such swellable dosage form attain the desired size within a short time, otherwise the dosage may pass through the pylorus and swell in the intestinal region which is undesirable. This application describes gastroretentive dosage form comprising the pH dependent graft copolymer. The dosage form floats and swells once it is placed in the medium which simulates acidic pH prevalent in the stomach, and maintains its integrity for the entire duration over which the drug is released from the dosage form.